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PurposeHigh consumption of fruits and vegetables decrease the risk of bladder cancer (BC). The evidence of specific fruits and vegetables and the BC risk is still limited.MethodsFruit and vegetable consumptions in relation to BC risk was examined by pooling individual participant data from case-control studies. Unconditional logistic regression was used to estimate study-specific odds ratio's (ORs) with 95% confidence intervals (CIs) and combined using a random-effects model for intakes of total fruits, total vegetables, and subgroups of fruits and vegetables.ResultsA total of 11 case-control studies were included, comprising 5637 BC cases and 10,504 controls. Overall, participants with the highest intakes versus the lowest intakes of fruits in total (OR 0.79; 95% CI 0.68-0.91), citrus fruits (OR 0.81; 95% CI 0.65-0.98), pome fruits (OR 0.76; 95% CI 0.65-0.87), and tropical fruits (OR 0.84; 95% CI 0.73-0.94) reduced the BC risk. Greater consumption of vegetables in total, and specifically shoot vegetables, was associated with decreased BC risk (OR 0.82; 95% CI 0.68-0.96 and OR 0.87; 95% CI 0.78-0.96, respectively). Substantial heterogeneity was observed for the associations between citrus fruits and total vegetables and BC risk.ConclusionThis comprehensive study provides compelling evidence that the consumption of fruits overall, citrus fruits, pome fruits and tropical fruits reduce the BC risk. Besides, evidence was found for an inverse association between total vegetables and shoot vegetables intake.

BackgroundElectronic learning (e-learning) is a widely accessible, low-cost option for learning remotely in various settings that allows interaction between an instructor and a learner. ObjectiveWe describe the development of a free and globally accessible multilingual e-learning module that provides education material on topics in pediatric endocrinology and diabetes and that is intended for first-line physicians and health workers but also trainees or medical specialists in resource-limited countries. MethodsAs complements to concise chapters, interactive vignettes were constructed, exemplifying clinical issues and pitfalls, with specific attention to the 3 levels of medical health care in resource-limited countries. The module is part of a large e-learning portal, ESPE e-learning, which is based on ILIAS (Integriertes Lern-, Informations- und Arbeitskooperations-System), an open-source web-based learning management system. Following a review by global experts, the content was translated by native French, Spanish, Swahili, and Chinese–speaking colleagues into their respective languages using a commercial web-based translation tool (SDL Trados Studio). ResultsPreliminary data suggest that the module is well received, particularly in targeted parts of the world and that active promotion to inform target users is warranted. ConclusionsThe e-learning module is a free globally accessible multilingual up-to-date tool for use in resource-limited countries that has been utilized thus far with success. Widespread use will require dissemination of the tool on a global scale.

BACKGROUND: Individuals with genetic neurodevelopmental disorders (GNDs) or intellectual disability (ID) are often affected by complex neuropsychiatric comorbidities. Targeted treatments are increasingly available, but due to the heterogeneity of these patient populations, choosing a key outcome and corresponding outcome measurement instrument remains challenging. OBJECTIVES: The aim of this scoping review was to describe the research on outcomes and instruments used in clinical trials in GNDs and ID. ELIGIBILITY CRITERIA: Clinical trials in individuals with GNDs and ID for any intervention over the past 10 years were included in the review. SOURCES OF EVIDENCE: MEDLINE, PsycINFO, and Cochrane CENTRAL were searched. Titles and abstracts were independently screened for eligibility with a subsample of 10% double-screening for interrater reliability. Data from full texts were independently reviewed. Discrepancies were discussed until consensus was reached. CHARTING METHODS: Information was recorded on patient populations, interventions, designs, outcomes, measurement instruments, and type of reporter when applicable. Qualitative and descriptive analyses were performed. RESULTS: We included 312 studies reporting 91 different outcomes, with cognitive function most frequently measured (28%). Various outcome measurement instruments (n = 457) were used, with 288 in only a single clinical trial. There were 18 genetic condition-specific instruments and 16 measures were designed ad-hoc for one particular trial. Types of report included proxy-report (39%), self-report (22%), clinician-report (16%), observer-report (6%), self-assisted report (1%), or unknown (16%). CONCLUSION: This scoping review of current practice reveals a myriad of outcomes and outcome measurement instruments for clinical trials in GNDs and ID. This complicates generalization, evidence synthesis, and evaluation. It underlines the need for consensus on suitability, validity, and relevancy of instruments, ultimately resulting in a core outcome set. A series of steps is proposed to move from the myriad of measures to a more unified approach.

The Atlantic Meridional Overturning Circulation (AMOC) is considered to be a tipping element in the Earth system due to possible multiple (stable) equilibria. Here, we investigate the multiple equilibria window of the AMOC within a coupled ocean circulation–carbon cycle box model. We show that adding couplings between the ocean circulation and the carbon cycle model affects the multiple equilibria window of the AMOC. Increasing the total carbon content of the system widens the multiple equilibria window of the AMOC, since higher-atmospheric pCO2 values are accompanied by stronger freshwater forcing over the Atlantic Ocean. The important mechanisms behind the increase in the multiple equilibria window are the balance between the riverine source and the sediment sink of carbon and the sensitivity of the AMOC to freshwater forcing over the Atlantic Ocean. Our results suggest that changes in the marine carbon cycle can influence AMOC stability in future climates.

Abstract Background The evidence base for the relationship between psychosocial work factors and mental health focuses primarily on the general working population but little is known about young workers. The aim of this qualitative study is to identify psychosocial work factors that affect the mental health of young workers, with a focus on (1) novel factors of the psychosocial work environment that are relevant for young workers but have not been described in the literature and (2) experiences of psychosocial work factors associated with mental health that are specific to and typical for young workers. Methods Semi-structured interviews were held with 36 workers aged up to 30. Participants were asked to describe work situations that affected their mental health. Factors were identified using a combination of inductive and deductive coding and open-coded factors were mapped onto the Copenhagen Psychosocial Questionnaire (COPSOQ), which is widely used as a framework for psychosocial work factors. Results Most of the psychosocial factors mentioned by the young workers could be mapped onto the COPSOQ framework and were therefore similar to the general working population. Novel factors identified by this study were “Procedural support” and “Responsibility for others”. We also identified young-worker-specific experiences of psychosocial work factors associated with mental health (i.e. Quantitative Demands, Influence at Work, Commitment to the Workplace, Job Insecurity, Quality of work, Job satisfaction, and Vertical Trust). Lastly, young workers did not report the COPSOQ factor Insecurity over working conditions and Work-life conflict was reported as an indicator of mental health status rather than being perceived as a factor of the psychosocial work environment. Conclusions Psychosocial work factors and their influence on mental health reported by young workers in this qualitative study are comparable to what is reported for the general working population. There are however some young-worker-specific experiences of psychosocial work factors and two novel factors. The novel factors, “Procedural support” and “Responsibility for others” are not found in common psychosocial work factor frameworks and might be studied specifically in relation to young workers. Our results provide organisations with levers that can be used to create a psychosocial work environment that benefits the mental health of young workers.

Abstract Background Advances in understanding the etiology of intellectual disability (ID) has led to insights in potential (targeted) treatments and personalized care. Implications of ID on health are often complex and require a multidisciplinary approach. The aim was to investigate the reporting of genetic diagnoses in multidisciplinary ID care and to identify associated clinical and demographic factors. Methods A retrospective chart review was performed on a randomly selected sample of individuals (n = 380) of a large ID care organization in the Netherlands. Data on genetic etiology, including genetic testing and diagnoses, and clinical and demographic characteristics were collected from files held by multidisciplinary team members. Results Reports on genetic etiology were available in 40% of the study sample (n = 151), with a genetic diagnosis recorded in 34% (n = 51), which is 13% of the total sample. In those with reported genetic diagnoses, this was reported in 90% of medical, 39% of psychodiagnostic, and 75% of professional caregivers’ files. Older age, mild ID, and the legal representative not being a family member were associated with less reported information on genetic etiology. Conclusions This study revealed that genetic diagnoses were often not reported in ID care files. Recommendations were formulated to reduce delay in diagnosis, and enable personalized care for individuals with ID.

OBJECTIVES: This study examined the associations between implemented disability-related policies and practices (DPP) and sustained employment among partially disabled employees in The Netherlands. METHODS: Employer survey data on implemented DPP were linked to register data on employment outcomes of partially disabled employees (N=6103 employees from N=366 employers). DPP included six domains based on 48 elements: sick leave policy, occupational health and safety services (OHS), prevention policy, reintegration policy, reintegration practices within the current employer and reintegration practices towards another employer. DPP domains were standardized on a 0–1 scale. Separate logistic regression models were estimated for DDP domains on one-year sustained employment adjusted for employee characteristics, firm size, and sector. RESULTS: Almost all organizations implemented at least one element of DPP on prevention policy, OHS, sick leave policy, and reintegration practices within the current employer, and two-thirds on reintegration policy and reintegration practices towards another employer. Implemented DPP on prevention policy [odds ratio (OR) 2.3, 95% confidence interval (CI) 1.3–4.0], OHS (OR 1.9, 95% CI 1.1–3.2), and sick leave policy (OR 1.8, 95% CI 1.0–3.3) were positively associated with sustained employment. No significant results were found for reintegration policy and both reintegration practices domains. Stratified analysis showed that DDP domains were particularly associated with sustained employment in larger organizations and in the private sector. CONCLUSIONS: Implemented DPP related to sick leave policy, OHS and prevention policy are associated with sustained employment among partially disabled employees, in particular in larger organizations and in the private sector.

OBJECTIVE: This paper presents an overview of 50 years of research on psychosocial working conditions and health with regards to conceptualization, interventions and policy. We reflect on the promise of past and current research on psychosocial working conditions and, in addition, discuss current progress in translating this research into workplace practice and improvements in people’s working lives. METHODS: We conducted a narrative review of meta-reviews and key publications on psychosocial working conditions and health. The review covers a historical overview of theories of the past 50 years, measurement of psychosocial working conditions, health effects, intervention research, and policy development on psychosocial working conditions. RESULTS: Psychosocial working conditions are conceptualized in different ways, with increasing complexity in the understanding developing over time. Exposures related to psychosocial working conditions are associated with a wide range of health outcomes, in particular cardiovascular disease and mental health conditions. In response to growing evidence on associations between psychosocial working conditions and health outcomes, intervention research has expanded rapidly, but for various reasons the evidence base is stronger and more extensive for individual- than organizational-level interventions. This individual/organizational imbalance is reflected in practice, and may partly explain why policy interventions have yet to show reductions in exposures to psychosocial work factors and associated adverse outcomes. CONCLUSIONS: Pressing needs for advancing the field include improvements in capturing exposure dynamics, developing objective measures of exposure, methodologic advancements to optimize causal inference in etiologic studies, and alternatives to randomized controlled trials for intervention evaluation.

Abstract Tissue surface tension influences cell sorting and tissue fusion. Earlier mechanical studies suggest that multicellular spheroids actively reinforce their surface tension with applied force. Here we study this open question through high-throughput microfluidic micropipette aspiration measurements on cell spheroids to identify the role of force duration and spheroid deformability. In particular, we aspirate spheroid protrusions of mice fibroblast NIH3T3 and human embryonic HEK293T homogeneous cell spheroids into micron-sized capillaries for different pressures and monitor their viscoelastic creep behavior. We find that larger spheroid deformations lead to faster cellular retraction once the pressure is released, regardless of the applied force. Additionally, less deformable NIH3T3 cell spheroids with an increased expression level of alpha-smooth muscle actin, a cytoskeletal protein upregulating cellular contractility, also demonstrate slower cellular retraction after pressure release for smaller spheroid deformations. Moreover, HEK293T cell spheroids only display cellular retraction at larger pressures with larger spheroid deformations, despite an additional increase in viscosity at these larger pressures. These new insights demonstrate that spheroid viscoelasticity is deformation-dependent and challenge whether surface tension truly reinforces at larger aspiration pressures.

Functional analyses are the main method to classify mismatch repair (MMR) gene variants of uncertain significance (VUSs). However, the pathogenicity remains unclear for many variants because of conflicting results between clinical, molecular, and functional data. In this study, we evaluated whether whole exome sequencing (WES) could add another layer of evidence to elucidate the pathogenicity of MMR variants with conflicting interpretations. WES was performed on formalin-fixed paraffin-embedded tumor tissue of eight patients with a constitutional MMR VUS (seven families), including eight colorectal and two endometrial carcinomas and one ovarian carcinoma. Cell-free CIMRA assays were performed to assign Odds of Pathogenicity to these VUSs. In four families, seven tumors showed MMR deficiency-associated mutational signatures, supporting the pathogenicity of the VUS. Moreover, somatic (second) MMR hits identified in the WES data were found to explain MMR staining patterns when the MMR staining was discordant with the reported germline MMR gene variant. In conclusion, WES did not significantly reclassify VUS in these cases but clarified some phenotypic aspects such as age of onset and explanations in case of discordant MMR stainings.

Background 22q11.2 deletion syndrome (22q11.2DS) is associated with cognitive impairments and an increased risk of psychopathology. Most of the research has been conducted in children and adolescents, although the majority of affected individuals live well into adulthood. Hence, limited data are available on functional outcomes in adults. Aims To provide more insight in cognitive and adaptive abilities, and daily life functioning (marital status, living situation and work situation) in adults with 22q11.2DS. Method This retrospective study included 250 Dutch-speaking adults (16–69 years) with 22q11.2DS from three sites in The Netherlands and Belgium. Data on full-scale IQ (FSIQ) scores (assessed with the Wechsler Adult Intelligence Scale), adaptive functioning (assessed with the Vineland Adaptive Behavior Scale II), and functional outcomes including marital status, living and work situation were systematically collected from clinical files. In addition, we examined predictors of adaptive functioning. Results The majority of individuals in our adult sample demonstrated a low level of adaptive functioning (65%). In contrast to previous findings in children and adolescents, the majority functioned at an intellectual disability level (56%). Male sex, lower FSIQ and autism spectrum disorder were predictors of lower adaptive functioning (P = 0.016, P < 0.001 and P = 0.16, respectively). Conclusions These results suggest that low levels of cognitive and adaptive functioning are common in adults with 22q11.2DS. Future longitudinal and multicentre studies including older patients (>40 years) are needed to further investigate cognitive and adaptive trajectories and their interactions with physical and psychiatric comorbidities.

Gaucher disease (GD) is a lysosomal storage disorder (LSD) resulting from inherited glucocerebrosidase (GBA1) deficiency. GD diagnosis relies on GBA1 activity assays, typically employing 4-methylumbelliferyl-β-D-glucopyranoside (4MU-β-Glc) as fluorogenic substrate. However, these assays suffer from background 4MU release by the non-lysosomal GBA2 and cytosolic GBA3 enzymes. Here we developed GBA1-selective fluorogenic substrates by synthesizing a series of 6-O-acyl-4MU-β-Glc substrates with diverse fatty acid tails. Because of the chemical and enzymatic instability of the ester bonds, analogs of 6-O-palmitoyl-4MU-β-Glc (3) with different chemical linkages were synthesized. 6-O-alkyl-4MU-β-Glc 9, featuring an ether linkage, emerged as the most optimal GBA1 substrate, exhibiting both a low Km and compared to substrate 3 a high Vmax. Importantly, substrate 9 is not hydrolyzed by GBA2 and GBA3 and therefore acts as a superior substrate for GD diagnosis. Plants contain glycosyl phytosterols (campesterol, β-sitosterol, and sigmasterol) that may also be acylated at C-6. LC-MS/MS analysis revealed that 6-O-acylated and regular glycosylcholesterol (HexChol) tend to be increased in spleens of patients with GD. Moreover, significant increases in 6-O-acyl-glycosyl-phytosterols were detected in GD spleens. Our findings suggest uptake of (6-O-acyl)-glycosyl-phytosterols from plant food and subsequent lysosomal processing by GBA1, and comprise the first example of accumulation of an exogenous class of glycolipids in GD. Excessive exposure of rodents to glycosylated phytosterols has been reported to induce manifestations of Parkinson’s disease (PD). Further investigation is warranted to determine whether (6-O-acyl)-glycosyl-phytosterols could contribute to the enigmatic link between inherited defects in GBA1 and the risk for PD.